Pyrimidinyl acetic acid derivatives and processes for their production

ABSTRACT

Process for preparing pyrimidinyl acetic acid derivatives which comprises treating a guanidine of the formula:   or a salt thereof, with citric acid in a strongly acidic medium, wherein R is an amino, hydrocarbylamino or dihydrocarbylamino radical, said hydrocarbyl-amino and dihydrocarbylamino radicals being unsubstituted, or substituted in the hydrocarbyl moiety with atoms or radicals which do not interfere with the process.

United States Patent [19] Parry Dec. 30, 1975 [54] PYRIMIDINYL ACETIC ACID DERIVATIVES AND PROCESSES FOR THEIR PRODUCTION [75] Inventor: David Rees Parry, Wokingham,

England [73] Assignee: Imperial Chemical Industries Limited, London, England 22 Filed: Dec. 26, 1973 21 Appl. N0.2 428,315

[30] Foreign Application Priority Data Jan. 8, 1973 United Kingdom 964/73 52 us. Cl. ..260/256.4 c; 260/2564 E; 260/2565 R; 424/251 [51] Int. Cl. C07D 239/36 [58] Field of Search 260/256.4 C

Turner, et al., Journ. Heterocyclic Chem., Vol. 9 (l), 1972, pp. 157-158.

Primary Examiner-Richard J. Gallagher Assistant Examiner-James H. Turnipseed Attorney, Agent, or Firm-Cushman, Darby & Cushman [57] ABSTRACT Process for preparing pyrimidinyl acetic acid derivatives which comprises treating a guanidine of the formula:

or a salt thereof, with citric acid in a strongly acidic medium, wherein R is an amino, hydrocarbylamino or dihydrocarbylamino radical, said hydrocarbyl-amino and dihydrocarbylamino radicals being unsubstituted, or substituted in the hydrocarbyl moiety with atoms or radicals which do not interfere with the process.

4 Claims, No Drawings PYRIMIDINYL ACETIC ACID DERIVATIVES AND PROCESSES FOR THEIR PRODUCTION This invention relates to a process for preparing py- 5 rimidine derivatives.

Accordingly the present invention provides a process for preparing a pyrimidine derivative of the formula:

which comprises treating a granidine of formula:

NH, =NH

or a salt thereof, with citric acid in a strongly acid medium, wherein R is an amino, hydrocarbylamino or dihydrocarbylamino radical, said hydrocarbylamino and dihydrocarbylamino radicals being unsubstituted, or substituted in the hydrocarbyl moiety with atoms or radicals which do not interfere with the process.

Preferred stongly acidic media in which the above invention process may be performed include concentrated sulphuric acid and oleum. I An especially preferred acidic medium is oleum. This is particularly effective when used at a rate of about 300-500 ml per g. mole of citric acid.

Preferably the process employs a slight molar excess (up to of citric acid with respect to the guanidine. The reaction may be carried out within a temperature range of 60100C, and preferably within a range of 65-80C. The time taken to completethe reaction depends upon the relative quantities of the reactants, but a period of from 1 to 4 hours is generally sufficient. Compounds which may be prepared by the above invention process include the following; 4-hydroxy-2-aminopyrimidin-6-yl acetic acid 4-hydroxy-Z-ethylaminopyrimidin-6-yl acetic acid 4-hydroxy-2-dimethylaminopyrim idin-6,-yl acetic acid 4-hydroxy-2-diethylaminopyrimidin--yl acetic acid In a further feature the invention provides compounds of formula:

CH COOH wherein R has any of the meanings given hereinabove CH COOH wherein R is" a hydrocarbylamino or dihydrocarbylamino radical. Preferred hydrocarbylamino radicals are alkylamino radicals and preferred dihydrocarbylamino radicals are dialkylamino radicals.

p The invention particularly provides the following novel compounds. 4-Hydroxy-2-ethylaminopyrimidine- 6 -yl acetic acid, having the formula:

CH COOH 4-Hydroxy-Z-diethylaminopyrimidin--yl acetic acid, having the formula:

4-Hydroxy-2-dimethylaminopyrimidin-6-yl acetic acid, having the formula:

PT /N CH COOH The compounds of formula:

wherein R has any of the meanings given hereinbefore are useful as intermediates in the production of pesticides.

In particular 4-hydroxy-2-ethylaminopyrimidin-6-yl acetic acid may be used in the production of 0,0-diethyl 0 (Z-N-ethylacetamido)-4-methylpyrimidin-6-yl phosphorothionate, and 4-hydroxy-2-diethylaminopyrimidin-6-yl acetic acid may be used in the production of 0,0-dimethyl and 0,0-diethyl 0(2-diethylamino-4- methylpyrimidin-6-yl) phosphorothionate.

The compounds of formula:

may be converted to the corresponding 4-hydroxy-6- methylpyrimidines by decarboxylation. This may be achieved by heating the compound to itsmelting (de- 3 composition) point or by heating in a suitable solvent, for example, water, lower aliphatic alcohols, such as ethanol or butanol, lower aliphatic ketones such as methyl iso-butyl ketone, optionally in the presence of a base, for example an alkali metal carbonate or bicarbonate.

The decarboxylation is preferably carried out at the reflux point of the solvent, and the time required to achieve decarboxylation is generally within a period from I to hours. When water alone is used the time required is generally more than 10 hours, but when an organic solvent is present the decarboxylation occurs much more rapidly and is generally complete in less than 10 hours.

The 4-hydroxy-6-methyl pyrimidines thus produced may subsequently be acylated, for example with a phosphoryl halide, to produce pesticidal products.

In a preferred process both the decarboxylation and acylation steps are carried out in the same solvent and reaction vessel.

In a further aspect, therefore, the invention provides a process for the preparation of a compound of formula:

CH COOI-I to produce the corresponding 4-hydroxy-6-methylpyrimidine; and

2. treating the said corresponding 4-hydroxy-6- methyl pyrimidine thus produced with an acylating agent capable of providing the acyl radical Z; where both steps (I) and (2) are carried out in the same solvent or diluent, optionally in the presence of a base.

In the process defined immediately hereinabove an acylating agent includes, for example, a carboxylic acid anhydride, such as acetic anhydride, a carboxylic acid halide such as benzoyl chloride, a sulphur containing organic acid halide such as methane sulphonyl chloride and dimethylsulphamoyl chloride, a carbamic acid halide such as dimethylcarbamoyl chloride, an isothiocyanate such as methyl isothiocyanate, a phosphorus containing acid halide such as dimethylphosphorothionochloridate or diethylphosphorothionochloridate or O,N-dimethylphosphoramidochloridate or dimethylphosphonothionochloridate.

Preferably the solvent or diluent used in this process is a non-reacting one, and preferred solvents are ketones such as methyl isobutyl ketone and acetone, or halogenated compounds such as carbon tetrachloride and chloroform. Where a base is present in the process it may be used in catalytic or molar proportions. A particularly useful base is an alkali metal carbonate.

In a preferred aspect the invention provides a process for the preparation of a compound of formula:

wherein R has any of the meanings given hereinbefore, and R is methyl or ethyl, which comprises the steps of: l. suspending or dissolving a compound of formula:

HO R

CH COOI-I in a suitable solvent or diluent and heating the mixture so obtained, optionally in the presence of a base, to effect decarboxylation of the compound; and

2. thereafter treating the mixture with a compound of formula:

EXAMPLE 1 This Example illustrates the preparation of 4- hydroxy-2-diethylaminopyrimidin-6-yl acetic acid.

Powdered citric acid monohydrate (42.0 g) was added in small portions over 1 hour to concentrated sulphuric acid (180 ml) at 0C and the mixture stirred until a clear solution was obtained. N,N-Diethylguanidine sulphate (32.8 g) was added over 15 minutes and the solution stirred for 1 hour at the ambient temperature (ca 2224C) and then at C for a further 2 hours. After dilution of the mixture with deionised water (l050 ml), ammonia solution (s.g. 0.880) was added to adjust the ph to 4, and the mixture cooled to 0C for 1 hour. The precipitate was collected by filtration, washed with ice-water (20 ml), acetone ml), and with ether (100 ml) to yield 4-hydroxy-2-diethylaminopyrimidin-o-yl acetic acid as a white powder, having a melting point (with decomposition) of l56-l57C.

EXAMPLE 2 This Example illustrates the conversion of the product of Example 1 to 4-hydroxy-2-diethylamino-6- methylpyrimidine.

4-l-lydroxy-2-diethylaminopyrimidin-6-yl acetic acid (4.0 g) was suspended in ethanol (50 ml) and the mixture refluxed for 16 hours. The volatile portion of the mixture was then evaporated under reduced pressure to yield 4-hydroxy-2-diethylamino-6-methyl pyrimidine as a white power, melting at 135C.

EXAMPLE 3 This Example illustrates the preparation of 4- hydroxy-2-diethylamino-6-methylpyrimidine from citric acid without isolation of the intermediate pyrimidine acetic acid.

Powdered citric acid monohydrate (21.0 g) was added in small portions to stirred concentrated sulphuric acid (50 ml) whilst the mixture temperature was maintained at 0C by external cooling over a period of 45 minutes. The mixture was then stirred for a further 30 minutes until a clear solution was obtained, after which diethylguanidine sulphate (16.4 g) was added over minutes, and the mixture was allowed to warm to the ambient temperature over a period of 1 hour. The mixture was then heated at 80-90C for 2 hours, during which time evolution of a gas was noted. The mixture was then cooled, diluted with deionised water (300 ml) and the pH adjusted to 4 with aqueous ammonia solution (s.g. 0.880). The resultant slurry was refluxed for 3.5 hours, during which the solid precipitate slowly dissolved. The mixture was then cooled and the precipitate which was deposited collected by filtration. The aqueous filtrate was extracted with chloroform (3 X 100 ml). The material which had been collected by filtration was dissolved in the minimum quantity of cold chloroform and this solution was combined with the chloroform extract. The combined chloroform solution was washed with 10% w/v aqueous sodium bicarbonate solution, and with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield chromatographically pure 4-hydroxy-2-diethylamino-6-methylpyrimidine, melting at 135C.

EXAMPLE 4 This Example illustrates the preparation of 4- hydroxy-2-ethylaminopyrimidin--yl acetic acid.

Using a procedure similar to that illustrated in Example 1 above, citric acid monohydrate (21.0 g) was reacted with monoethylguanidine sulphate (13.6 g) in concentrated sulphuric acid (60 ml). 4-Hydroxy-2- ethylaminopyrimidin-6-yl acetic acid was precipitated from the diluted mixture by adjusting the pH to 3.5 with concentrated aqueous ammonia solution (s.g. 0.880), and collected by filtration. It melted with decomposition at 169l 70C.

EXAMPLE 5 This Example illustrates the conversion of the product of Example 4 into 4-hydroxy-2-ethylamino-6- methylpyrimidine.

4-Hydroxy-2-ethylaminopyrimidin-6-yl acetic acid was suspended in ethanol (50 ml) and the mixture refluxed for 16 hours. Evaporation of the ethanol under reduced pressure yielded chromatographically pure 4-hydroxy-2-ethylamino-6-methylpyrimidine, melting at 176C.

EXAMPLE 6 This Example illustrates the preparation of 4- hydroxy-Zdiethylamino-6-methylpyrimidine.

A -mixture of citric acid monohydrate (126.0 g) and diethylguanidine sulphate (82.0 g) was added to 15% oleum (250 ml), keeping the temperature below 30C by external cooling. After stirring at the ambient temperature for 15 minutes to complete solubilisation the solution was heated at C for minutes, cooled by external cooling to 0C, and carefully diluted with water (350 ml) and with ammonia solution (s.g. 0.880, 600 ml). The resulting slurry was heated to reflux, methyl isobutyl ketone (10 ml) being added to prevent excessive frothing. Refluxing was continued for 16 hours, after which the mixture was cooled to 7080C and methyl isobutyl ketone (600 ml) added to dissolve the precipitate. The ketonic phase was separated, washed with water (2 X 100 ml) whilst still hot, and then cooled and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded chromatographically pure 4-hydroxy-2-diethylamino-6 -methylpyrimidine, melting point 133-l35C.

EXAMPLE 7 This Example illustrates the preparation of 0,0- diethyl 0-2-diethylamino-6-methylpyrimidin-4-yl phosphorothionate.

A mixture of citric acid monohydrate (23.1 g) and diethylguanidine sulphate (16.4 g) was added quickly to 15% oleum (40 ml) causing the temperature to rise to 60C. The mixture was then heated at 70C for minutes after which the solution was cooled to 50C and diluted with water (40 ml) which caused the temperature to rise to 100C, and the mixture was maintained at this temperature whilst ammonia solution (s.g. 0.880) was added to bring the pH to 7. Methyl isobutyl ketone (5.0 ml) was added to the slurry thus produced and the solution was heated to reflux for 15 minutes after which a further quantity of methyl isobutyl ketone ml) was added and the refluxing continued for 75 minutes. The mixture was cooled to 80C, the aqueous phase removed and the ketonic phase washed with water (25 ml). The last traces of water were then removed by azeotropic distillation after which diethylphosphorochloridothionate (17.0 g) and anhydrous potassium carbonate (18.6 g) were added to the ketonic solution and the mixture stirred at 60C for 3 hours. The solid precipitate was removed by filtration, the filtrate washed with aqueous sodium hydroxide (2N, 75 ml), water (75 ml), dilute sulphuric acid (2N, 75 ml) and finally water (2 X 75 ml). The ketonic phase was dried over anhydrous magnesium sulphate, and the solvent removed by evaporation under reduced pressure to yield 0,0-diethyl 0-2-diethylamino-6- methylpyrimidin-4-yl phosphorothionate as a pale yellow oil, spectroscopically and chromatographically identical with an authentic sample.

I claim:

1. A pyrimidine derivative of the formula:

HO N R \W CH COOH wherein R is alkylamino or dialkylamino wherein the alkyl moiety is methyl or ethyl. 

1. A PYRIMIDINE DERIVATIVE OF THE FORMULA:
 2. 4-Hydroxy- 2-ethylaminopyrimidin-6-yl acetic acid.
 3. 4-Hydroxy-2-diethylaminopyrimidin-6-yl acetic acid.
 4. 4-Hydroxy-2-dimethylaminopyrimidin-6-yl acetic acid. 